Keratoconus is the most common degenerative disease affecting the cornea. This condition tends to develop around puberty and to progress over the next few decades, but its clinical history can be quite variable. As keratoconus develops, the cornea thins and bulges. Eventually, a corneal transplant may be needed to maintain vision. In its earliest stages, the disease is particularly difficult to detect, even using state-of-the-art diagnostic techniques such as anterior/posterior surface topography. This is of great importance to the corneal refractive surgeon because surgical treatment of an occult keratoconic cornea will weaken it and greatly accelerate the occurrence of symptoms. Because of the difficulty in differentiating early keratoconus from atypical normal corneas, many normal eyes deemed 'suspicious' are denied treatment. At the same time, some keratoconic eyes are missed and operated upon, with disastrous consequences. Early detection of keratoconus may also benefit patients because of the recent development of methods for strengthening the corneal stroma and preventing disease progression. We have developed a technique based on the use of high resolution ultrasound for imaging the cornea and measuring the thickness of its component layers, including the epithelium (about 50 microns in thickness) and the stroma (about 500 microns in thickness). We have shown that the epithelium, which is the surface layer of the cornea, will remodel itself to smooth out underlying irregularities. In early keratoconus, as the anterior stromal surface begins to bulge forward, the epithelium will thin above the apex of the bulge and thicken around it, to maintain a smooth anterior surface. This compensatory mechanism prevents anterior surface topography from detecting keratoconus in its early stages. We have also developed methods for characterizing the elastic properties of the cornea by inducing and measuring surface displacements in response to a pulse of acoustic radiation force. We will further develop and test this technique and apply it clinically in conjunction with the Ocular Response Analyzer, an instrument that causes a similar effect by use of an air pressure pulse. This proposal will involve analysis of topographic and pachymetric patterns and elastic properties in normal, keratoconus and keratoconus-suspicious eyes. We will develop an index based on multivariate analysis of these patterns based on unambiguously classified cases, and validate the risk index on suspicious cases based on clinical documentation of disease progression. Our goal is to reduce the percentage of screened cases deemed keratoconus- suspicious by at least a factor of two by allowing an unambiguous diagnosis of early keratoconus. PUBLIC HEALTH RELEVANCE: Keratoconus (KC) is a corneal dystrophy will in many cases ultimately require corneal transplantation to maintain vision. Early detection, which is not possible with current technology, would allow early treatment and prevent sever damage to KC corneas inadvertently operated upon for correction of vision. Our aim is to combine measurements of corneal elasticity, topography and epithelial thickness to develop means for early detection of KC.